WO2007105551A1

WO2007105551A1 - Novel pyridine derivative having anti-helicobacter pylori activity

Info

Publication number: WO2007105551A1
Application number: PCT/JP2007/054387
Authority: WO
Inventors: Masaharu Ito; Masaichi Yamamoto
Original assignee: Arigen Pharmaceuticals, Inc.
Priority date: 2006-03-10
Filing date: 2007-03-07
Publication date: 2007-09-20
Also published as: ES2374730T3; US20090143438A1; SI2003130T1; CA2645467C; JP5053992B2; PL2003130T3; RU2008140164A; KR101348643B1; JPWO2007105551A1; MX2008011594A; EP2003130A2; CA2645467A1; BRPI0708601A2; KR20090005292A; ATE533757T1; AU2007225935B2; AU2007225935A1; HK1122290A1; RU2433126C2; EP2003130B1

Abstract

The object is to provide an excellent pharmaceutical having an anti-Helicobacter pylori activity. Disclosed is a novel pyridine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof, which has a potent antibacterial activity against H. pyroli (Helicobacter pyroli): (I) wherein R represents a linear or branched hydroxyalkyl group having 5 to 10 carbon atoms. Examples of the disease which can be prevented/treated by administration of a pharmaceutical agent comprising the compound include gastritis, gastric ulcer, duodenal ulcer, gastric MALT lymphoma, gastric hyperplastic polyp, development of gastric cancer after endoscopic resection of the early stage of gastric cancer and the like.

Description

Specification

Anti-helicopactor · A novel pyridine derivative with pylori action

Technical field

[0001] The present invention relates to a novel pyridine derivative having an excellent anti-helicopacter pylori action, a method for producing the same, and a pharmaceutical composition containing the compound.

Background art

[0002] Gastritis, gastric ulcer, and duodenal ulcer are diseases that develop due to complex intertwining of factors such as stress, genetic predisposition, and lifestyle habits. In recent years, helicopter 'H. pylori' has been attracting attention as one of the causes. Since 1983, when Warren and Marshall succeeded in isolating and cultivating helical bacteria from gastric biopsy specimens, energetic research has been conducted on the relationship between gastritis, gastric ulcer, duodenal ulcer, and gastric cancer. As a result, H.pylori infection rate was about 4% in healthy stomach, 83% in chronic gastritis, 69% in gastric ulcer, 92% in duodenal ulcer, non-ulcer digestion The rate is as high as 51% for bad syndromes (Martin J. Blaser, Clin. Infectious Disease, 15; 386-393, 1992). In addition, H.pylori infection is strongly associated with the incidence of gastric cancer. In 1994, WHO's international cancer research institute made H.pylori a highly causal carcinogen.

[0003] Treatment for gastritis, gastric ulcers, duodenal ulcers, etc. is mainly for symptomatic therapy using drugs that suppress gastric acid secretion such as proton pump inhibitors and mucosal protective drugs that suppress gastric acid secretion. Met. However, even if the lesions are temporarily cured with these drugs, it is said that approximately 80% will relapse within one year if treatment is stopped (Martin J. Blaser,: Clin. Infectious Disease, 15; 386-393, 1992). On the other hand, after eradication of H. pylori (hericopactor 'H. pylori), the annual recurrence rate was reported to be within 10% for duodenal ulcers and clearly low for gastric ulcers (Graham DY et. : Ann.Intern.Med., 116; 705_708, 1992). Therefore, a method in which a large amount of antibacterial agents such as amoxicillin, clarithromycin, and methotral nidazole are simultaneously administered to a proton pump inhibitor (PPI) for a week or more has become widespread. However, large doses of antibacterial agents also kill useful bacteria in the intestinal tract. As a result, loose stool, diarrhea and abnormal taste, glossitis, stomatitis and liver dysfunction, liver dysfunction, bleeding There are concerns that it may promote side effects such as enteritis and the emergence of metacillin-resistant bacteria (MRSA).

[0004] Against this background, efforts have been made to develop highly safe drugs that exhibit sufficient antibacterial activity against H. pylori at ordinary doses. For example, Patent Documents 1 to 4 and 9 propose such drugs.

[0005] In order to exert H.pylori eradication effects equivalent to antibiotics in clinical practice, the activity is equivalent to or better than the anti-H.pylori activity of antibiotics that are clinically effective against H.pylori. Must be indicated. That is, it is desirable that the minimum growth inhibitory concentration (MIC) is 0.3 μg / m beam activity.

[0006] In addition, some of the guanidinomethylcyclohexanecarboxylic acid ester derivatives described in Patent Document 5 have anti-H.pylori activity of less than MIC force μg / ml. However, this compound has the property of decomposing very rapidly by degrading enzymes in the small intestine or blood. This property is described in Patent Document 6 "Antibiotics and synthetic antibacterial agents are metabolized such as those that pass through the digestive tract and are absorbed from the intestinal tract into the blood and excreted with feces. As it is distributed, long-term administration must be avoided as many of the bacteria inhabiting the intestine will be killed by the passage of the drug through the intestine and the balance of the intestinal flora will be lost. " It is a compound designed for the metabolic properties of degrading selectivity to H. pylori in the intestine or blood. However, the metabolic enzymes and enteric bacteria in the intestines and blood are known to vary from individual to individual and due to diet, and it is highly possible that such metabolic characteristics are stably guaranteed in patients with diverse patient backgrounds. Absent.

[0007] By the way, a pyridine derivative useful as an anti-ulcer agent (see Patent Document 7), a pyridine derivative exhibiting an antibacterial action against Helicopacter pylori (see Patent Document 2), and a pyridine derivative used for suppressing gastric acid secretion (Patent Document 2) Reference 8) is known. In addition, compounds 2-[{4- (2-hydroxyethoxy) -3-methylpyridine_2-yl} methylthio] -1H-benzimidazole (Comparative Compound 1) and 2-[{4- (3_Hydroxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole (Comparative Compound 2) is disclosed in Patent Document 9 as Examples 26 and 34 as antiulcer agents. Although it is a compound that is described as useful, there is no description of experimental data on its anti-ulcer activity. There is no description or suggestion regarding the action.

Patent Document 1: JP-A-2-209809

Patent Document 2: JP-A-3-173817

Patent Document 3: Japanese Patent Laid-Open No. 3-48680

Patent Document 4: JP-A-7-69888

Patent Document 5: International Publication No. 96/06825 Pamphlet

Patent Document 6: International Publication No. 97/23207 Pamphlet

Patent Document 7: JP-A 61-50979

Patent Document 8: JP-A-58-39622

Patent Document 9: Japanese Patent Laid-Open No. 5-247035

Disclosure of the invention

Problems to be solved by the invention

In view of such circumstances, the present inventors have shown that anti-H.pyroli activity is strong at MIC of less than 0.3 μg / ml and does not act on human resident bacteria. The present inventors have succeeded in searching for a compound exhibiting an antibacterial action specifically, and found a substance that is also effective against antibiotic-resistant bacteria such as roxithromycin and ofloxacin, thereby completing the present invention.

That is, an object of the present invention is to provide a compound exhibiting an excellent antibacterial action against H.pyroli, and a pharmaceutical composition containing the compound.

Means for solving the problem

The present invention provides the following inventions (1) to (12).

[0011] (1) General formula (I)

[Chemical 1]

[In the formula, R represents a linear or branched hydroxyalkyl group having 5 to 10 carbon atoms] Or a pharmaceutically acceptable salt thereof.

[0013] (2) Formula (II)

[Chemical 2]

[0014] and the general formula (ΙΠ)

[Chemical 3]

[0015] (wherein R represents a linear or branched hydroxyalkyl group having 5 to 10 carbon atoms, and X represents a halogen atom or a sulfonoxy group). The general formula (I)

[Chemical 4]

[0016] A method for producing a novel pyridine derivative represented by the formula (wherein R represents the same meaning as described above) or a pharmaceutically acceptable salt thereof.

[0017] (3) A pharmaceutical composition comprising the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1).

[0018] (4) An anti-helicobacter pylori 1J comprising the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1).

[0019] (5) The anti-helicopacter pylori agent according to (4), wherein the target Helicopacter pylori is a resistant bacterium to a macrolide antibiotic or a new quinolone antibiotic. [0020] (6) The anti-helicopactor 'pillary agent according to (4), further comprising one or more dextrins.

[0021] (7) The anti-helicobacter pylori agent according to (4), further containing one or more drugs for suppressing gastric acid secretion.

[0022] (8) A preventive or therapeutic agent for a disease involving Helicopacter pylori comprising the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) as an active ingredient.

[0023] (9) The disease is gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia syndrome, gastric MALT lymphoma, gastric hyperplasia polyp, gastric cancer, gastrointestinal cancer, vaginitis, or inflammatory bowel disease, (8) The preventive or therapeutic agent as described.

[0024] (10) The preventive or therapeutic agent according to (9), wherein the gastric cancer is gastric cancer that occurs after endoscopic resection of early gastric cancer.

[0025] (11) The preventive or therapeutic agent according to any one of (8) to (10), further comprising one or more dextrins.

[0026] (12) The prophylactic or therapeutic agent according to any one of (8) to (10), further containing one or more drugs that inhibit gastric acid secretion.

[0027] (13) A method for preventing or treating a disease in a mammal, comprising administering the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) to the mammal.

[0028] (14) The method according to (13), further comprising administering one or two or more dextrins, or one or more drugs for suppressing gastric acid secretion.

[0029] (15) An amount of the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) effective for sterilizing or sterilizing Helicobacter pylori, a mammal in need thereof A method for sterilizing or sterilizing Helicopacter pylori in mammals, comprising:

[0030] (16) The method according to (15), further comprising administering one or two or more dextrins, or one or more drugs for suppressing gastric acid secretion.

[0031] (17) The novel pyridine derivative or the pharmaceutically acceptable salt thereof described in (1) is required in an amount effective for preventing or treating a disease involving Helicobacter pylori. A method for preventing or treating a disease associated with Helicobacter pylori in a mammal, comprising administering to a mammal. [0032] (18) The method according to (17), further comprising administering one or two or more dextrins, or one or more drugs for suppressing gastric acid secretion.

[0033] (19) Use of the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) for the manufacture of a medicament.

[0034] (20) The novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) is one or more dextrins, or one of drugs that suppress the secretion of gastric acid or Use according to (19), used in combination with two or more.

[0035] (21) The use according to (19) or (20), wherein the medicament is a medicament for the prevention or treatment of a disease involving Helicopacter pylori.

[0036] (22) Use of the novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) for the production of an anti-helicopacter pylori agent.

[0037] (23) The novel pyridine derivative or a pharmaceutically acceptable salt thereof described in (1) is one or more dextrins, or one of drugs that suppress the secretion of gastric acid or Use according to (22), used in combination with two or more.

[0038] (24) The novel pyridine derivative described in (1) or a pharmaceutically acceptable salt thereof and that used for sterilization or sterilization of Helicobacter pylori Product with a written description or packaging container.

[0039] (25) The novel pyridine derivative described in (1) or a pharmaceutically acceptable salt thereof, and the pyridine derivative used for the prevention or treatment of a disease involving Helicobacter pylori. Product with written instructions or packaging container.

The invention's effect

[0040] The novel pyridine derivative of the present invention and a pharmaceutically acceptable salt thereof show an excellent antibacterial action against H.pyroli (helicobutter pylori). The novel pyridine derivative of the present invention and its pharmaceutically acceptable salt do not act on human resident bacteria, and have an extremely excellent advantage as a medicament that specifically exhibits antibacterial activity against H.pyroli. It also has the advantage of exhibiting excellent antibacterial activity against H.pyroli, which is resistant to macrolide antibiotics or new quinolone antibacterial agents. Furthermore, by using the novel pyridine derivative of the present invention and pharmaceutically acceptable salts thereof, H.pyr in mammals (especially humans) oli can be sterilized.

[0041] This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2006-66431, which is the basis for the priority of the present application.

BEST MODE FOR CARRYING OUT THE INVENTION

[0042] R in the formula (I) or (III) represents a linear or branched hydroxyalkyl group having 5 to 10 carbon atoms. In the present invention, the term “linear or branched hydroxyalkyl group having 5 to 10 carbon atoms” means that at least one hydrogen group of the linear or branched alkyl group having 5 to 10 carbon atoms is a hydroxyl group. A substituted group. The number of hydroxy group on the hydroxyalkyl group is not particularly limited, but 1 to 3 is preferable 1 or 2 is most preferable. The position of the hydroxyl group in the hydroxyalkyl group is not particularly limited, and may be present at any position on the carbon chain. However, one hydroxyl group (at least one of them if a plurality of hydroxyl groups are present) may be present. Is preferably present on the terminal carbon of the carbon chain. That is, at least one hydroxyl group on the hydroxyalkyl group is a group formed by substituting a hydrogen group on —CH at the end of a linear or branched alkyl group having 5 to 10 carbon atoms. Preferably there is. The carbon number of R group is

Three

Any force within the range of 5 to 10 is suitable force S, and particularly preferred is carbon number 8. The number of carbons in the R group is preferably in the range of 5 to 10 from the viewpoint of the strength of anti-helicopacter pylori activity. The number of carbons in the range of 6 to 9 is more preferable. Is particularly preferred. The R group may be either linear or branched, but is particularly preferably linear. Particularly preferred as the R group is, for example, _ (CH 3)

twenty five

H,-(CH) OH,-(CH) OH,-(CH) OH,-(CH) OH,-(CH) OH force S.

2 6 2 7 2 8 2 9 2 10

[0043] In the above formula (m), X represents a halogen atom or a sulfodioxy group. The halogen atom means any one of fluorine, chlorine, bromine and iodine. As the sulfonyloxy group, various sulfodioxy groups can be used. Typically, an alkylsulfonyloxy group which may be substituted with a substituent or an arylsulfonyloxy which may be substituted with a substituent. A xy group can be used. Specifically, examples of the alkylsulfonyloxy group include lower alkylsulfonyloxy groups such as methanesulfonyloxy group and ethanesulfonyloxy group. The alkyl contained in the alkylsulfonyloxy group is Furthermore, it may be substituted with a substituent such as halogen. Examples of the arylsulfonyloxy group include a benzenesulfonyloxy group. The aryl contained in the arylsulfonyloxy group may be further substituted with a substituent.

[0044] The pyridine derivative (I), which is the target compound of the present invention, can be produced by reacting the starting compound (i) with (III). This reaction is conveniently carried out in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alcoholates such as t-butoxy potassium, propoxy sodium, ethoxy sodium and methoxy sodium; alkali metals such as potassium carbonate and sodium carbonate. And organic amines such as triethylamine. Examples of the solvent used in the reaction include alcohols such as methanol and ethanol, and dimethyl sulfoxide. The amount of base used in the above reaction is usually slightly more than 1 equivalent, but a large excess of base may be used. That is, 1 to 10 equivalents, more preferably 1 to 4 equivalents. The reaction temperature is usually from −40 ° C. to around the boiling point of the solvent used, more preferably from 0 ° C. to 60 ° C. The reaction time is about 0.2 to 24 hours, more preferably 0.5 to 2 hours.

[0045] The target compound (I) produced by the above reaction can be isolated and purified by conventional means such as recrystallization and chromatography.

[0046] The compound (I) of the present invention may be converted into a pharmacologically acceptable salt by commonly used means. Examples of the salt include hydrochloride, bromate, iodate, phosphate, nitrate, sulfate, acetate, citrate and the like.

[0047] The compound according to the present invention or a salt thereof may be in the form of a hydrate or a solvate with a lower alcohol or the like. The hydrate or solvate form is also included in the scope of the compound according to the present invention or a salt thereof.

[0048] Next, a method for producing the raw material composite (III) will be described.

[0049] Manufacturing method 1

[Chemical 5]

[0050] The chloro derivative (VI) can be obtained by reacting the nitro compound represented by the general formula (IV) with concentrated hydrochloric acid. By reacting the chloro derivative (VI) with an alcohol derivative ROH (IV) in the presence of a base, an alkoxy derivative of the general formula (VII) can be obtained. Examples of bases include alkali metals such as lithium, sodium and potassium; alkali metal hydrides such as sodium hydride and potassium hydride; such as t-butoxy potassium, propoxy sodium, ethoxy sodium and methoxy sodium. Alcoholates; carbonates or bicarbonates of alkali metals such as potassium carbonate, lithium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate; alkali metals such as potassium, sodium, lithium; sodium hydroxide, water Examples include alkali hydroxides such as potassium oxide. Solvents used in the reaction include the lower alcohol represented by ROH, ethers such as tetrahydrofuran, dioxane, and t_butyl methyl ether, ketones such as acetone and methyl ethyl ketone, benzene, toluene, Aromatic hydrocarbons such as xylene and trimethylbenzene are listed. Other usable solvents include acetonitrile, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidone and the like. The reaction temperature is appropriately selected from _70 ° C to the vicinity of the boiling point of the solvent. The reaction time is about 1 to 48 hours.

[0051] The compound (VII) thus obtained is added in the presence of acetic anhydride alone, an alkali metal acetate such as sodium acetate or acetic acid potassium, or a mineral acid such as sulfuric acid or perchloric acid. By heating (about 80 to 120 ° C), a 2-acetoxymethylviridine derivative represented by the general formula (vm) is obtained. The reaction time is usually about 0.1 to 10 hours.

[0052] Next, the 2-hydroxymethylpyridine derivative represented by the general formula (IX) can be produced by alkaline hydrolysis of the compound (VIII). Examples of the alkali include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and the like. Examples of the solvent used include methanol, ethanol, water and the like. The reaction time is about 0.1 to 2 hours.

[0053] Further, by halogenating compound (IX) with a chlorinating agent such as thionyl chloride, a brominating agent or an iodinating agent, a 2-halogenomethylviridine derivative represented by the general formula (ΠΙ) is produced. Power S can be. Alternatively, it can be sulfonylated with various sulfonoxy agents, for example, alkylsulfonyloxylating agents such as methanesulfuryl chloride and ethanesulfonyl chloride, or aromatic sulfonyloxylating agents such as benzenesulfonyl chloride. Thus, a 2-sulfonoxyloxymethyl pyridine derivative represented by the general formula (III) can be produced. Examples of the solvent used include chloroform, formaldehyde, dichloromethane, tetrachloroethane, benzene, toluene, tetrahydrofuran, dioxane, methinole t-butinoleate, dioxane, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and the like. The reaction temperature is usually selected from an appropriate temperature from -70 ° C to around the boiling point of the solvent. The reaction time is about 0.1 to 2 hours.

[0054] The compound of the present invention or a salt thereof can sterilize or sterilize Helicopacter pylori in the body of an animal belonging to a mammal (typically a human). That is, the compound of the present invention or a salt thereof is effective as an anti-helicopacter pylori agent.

[0055] The present invention is also a method for sterilizing or sterilizing Helicopacter pylori in a mammal, wherein an effective amount of the compound of the present invention or a salt thereof is administered to a mammal in need of the method. A method comprising administering is provided.

[0056] The present invention also provides the use of a compound of the present invention or a salt thereof in the manufacture of an anti-helicopacter pylori agent.

[0057] The drug containing the compound of the present invention or a salt thereof is effective for preventing or treating a disease involving Helicopacter pylori. According to the present invention, “Helicopter pylori” “Disease involving” refers to a disease caused or exacerbated by Helicopacter pylori infection, survival or growth in vivo. In other words, a “disease related to Helicopacter pylori” is a disease whose symptoms can be improved by removing Helicopacter pylori. Examples of such diseases include gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia syndrome, gastric MALT lymphoma, gastric hyperplasia polyp, gastric cancer (especially gastric cancer that occurs after endoscopic removal of early gastric cancer), etc. Can be mentioned. Other examples of “diseases involving Helicopactor pylori” include gastrointestinal cancer caused by Helicopacter pylori and vaginitis. The compound of the present invention or a salt thereof can suppress or prevent the progression of gastrointestinal cancer caused by Helicopacter pylori. Other examples of “diseases involving Helicopacter pylori” include inflammatory bowel disease caused by Helicobacter pylori.

[0058] When the compound of the present invention is used as a medicine, various dosage forms can be adopted depending on the purpose of prevention or treatment. Examples of dosage forms include powders, fine granules, granules, tablets, Capsule, dry syrup simultaneous IJ, syrup, injection and the like. Pharmaceutical compositions containing the compounds of the present invention may include pharmaceutically acceptable carriers or excipients, or other additives.

[0059] When preparing an oral solid preparation, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added to the compound of the present invention, if necessary. Tablets, coated tablets, granules, powders, capsules and the like can be produced by conventional methods. Such additives may be those commonly used in the art. For example, corn starch, lactose, sucrose, sodium chloride salt, mannitol, sorbitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like can be used as excipients. Binders include: water, ethanol, gum arabic, tragan, propanol, simple syrup, glucose solution, starch: ^ night, gelatin f night, canoleboxy methinorescenellose, hydroxypropinoresenololose, gelatin, hydroxy Propinorestarch, methinorescenellose, ethinoresenorelose, shellac, calcium phosphate, polybulal alcohol, polybull ether, polyvinylpyrrolidone and the like can be used. Disintegrating agents include gelatin powder, crystalline cellulose, dry starch, sodium alginate, pectin, agar powder, carboxymethylcellulose, sodium bicarbonate, calcium carbonate, calcium citrate, sodium lauryl sulfate, stearic acid Monoglyceride, lactose and the like can be used. As the lubricant, silica, purified talc, stearate, borax, polyethylene glycol and the like can be used. As the colorant, those permitted to be added such as titanium oxide and iron oxide can be used. As a flavoring agent, sucrose, orange peel, citrate, tartaric acid and the like can be used.

[0060] When preparing an oral liquid preparation, a liquid preparation, a syrup, an elixir or the like is produced by a conventional method by adding a corrigent, a buffer, a stabilizer, a corrigent, etc. to the compound of the present invention. Power S can be. In this case, the flavoring agent may be those listed above. Examples of the buffer include sodium quenate. Stabilizers include tragacanth, arabic gum, gelatin and the like.

[0061] When an injection is prepared, a pH adjuster, buffer, stabilizer, tonicity agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous are added by a conventional method. It is possible to produce injections for medical use. Examples of the pH adjuster and buffer in this case include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of local anesthetics include hydrochloride pro-in and lidocaine hydrochloride. Examples of the isotonic agent include sodium chloride salt and sugar.

[0062] In addition to the novel pyridine derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the pharmaceutical composition and the preventive or therapeutic agent of the present invention described in the claims include one kind Or it can further contain two or more dextrins. Examples of dextrin that can be used in the present invention include α-dextrin, -dextrin, γ_dextrin, α-cyclodextrin, -cyclodextrin, γ-cyclodextrin, and the like. Not.

[0063] Further, the pharmaceutical composition and the preventive or therapeutic agent of the present invention described in the claims are added to the novel pyridine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. One or more drugs that suppress the secretion of gastric acid can be further contained. Examples of drugs that suppress gastric acid secretion include H2 blockers and proton pump inhibitors. Examples of H2 blockers that can be used in the present invention include famotidine and ranitidine as proton pump inhibitors that can be used in the present invention. Examples thereof include, but are not limited to, lansoprazole, omebrazole, rabebrazole, pantoprazole and the like.

[0064] According to the combination preparation as described above, the effect of the present invention is expected to be further enhanced.

[0065] The amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which the dosage form is to be applied, or the dosage form thereof, but is generally per dosage unit form. For oral preparations, the dosage is preferably about 1 to 1200 mg and for injections about 0.1 to 500 mg. In addition, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., but cannot be determined unconditionally, but is usually about 0.1 to 5000 mg per day for adults, preferably It should be 1200 mg, and it is preferable to administer this once a day or in 2 to 4 divided doses.

Example

[0066] Next, the raw material compounds, comparative compounds, and methods for producing the compounds of the present invention used in the present invention will be specifically described with reference to synthesis examples and examples. The HPLC analysis was performed under the following conditions.

[0067] Column Inertsil ODS-3 150mmx4.6mmID

Eluent 0.05MKH PO / acetonitrile = 50/50 (v / v)

twenty four

Flow rate l.OmL / min.

Column temperature 40 ° C

Injection amount

Detection wavelength 254nm

Synthesis Example 1: 4- (5_Hydroxypentyloxy) -2.3-Dimethylpyridine-N-oxide

Under a nitrogen stream, 140 mL of 1,5-pentanediol was charged in a silicon oil bath and stirred, and 4.6 g (0.2 mol, 2.0 eq.) Of metal Na was added. Next, the silicon oil bath was heated and reacted at 100 ° C. for 1 hour. To the obtained reaction solution, 15.8 g (l.Omol, l.Oeq.) Of 4_chloro-2,3-dimethylpyridine-N-oxide was added, and the temperature was raised to 120 ° C and reacted for 2 hours. . After cooling the reaction solution, 53.3 g of the concentrated residue obtained by concentrating to dryness under reduced pressure was subjected to silica gel column purification to give 4- (5-hydroxypentyloxy) -2,3-dimethylviridine-N- 25.0 g of oxide was obtained. Synthesis Example 2: 4- (5-Hydroxypentyloxy) -2-acetoxymethyl-3-methylpyridine

Acetic anhydride 153.lg (1.5mol, 15eq.) Is added to 24.5g (O.lmol, l.Oeq.) Of 4- (5-hydroxypentyloxy) -2,3-dimethylviridine-N-oxide 100 ° C was allowed to react for 5 hours. The concentrated residue obtained after distilling off anhydrous acetic acid was purified on a silica gel column to obtain 12.lg of 4_ (5-hydroxypentyloxy) -2-acetoxymethyl-3-methylpyridine (yield 39.2%)

[0069] Synthesis Example 3: 4- (5-hydroxypentyloxy) -2-hydroxymethyl-3_methylpyridine

4- (5-hydroxypentyloxy) -2-acetoxymethyl-3-methylpyridine (11.8 g, 0.03 8 mol, l.Oeq.) Was added dropwise to 24.4 g (0.152 mol, 4.0 eq.) Of 20% aqueous sodium hydroxide. After reacting at room temperature for 1 hour, extract with 150 mL of chloroform, dry with magnesium sulfate, and concentrate to dryness to give 4_ (5-hydroxypentyloxy) -2-hydroxymethyl-3-me 6.8 g of tilpyridine was obtained as pale yellow crystals (yield 79.1%).

[0070] Synthesis Example 4: 4- (6-hydroxyhexyloxy) -2,3-dimethylviridine-N-oxide

Under a nitrogen stream, 1,6-hexanediol 47.3g (0.4mol, 4.0eq.) And toluene lOOmL were charged in a silicon oil bath and dissolved at 55 ° C with stirring, and then metal Na 4.6g (0.2mol, 2.0eq. eq.) was added in small portions over 2 hours. The temperature rose from 79 ° C to 91 ° C. Next, the silicon oil bath was heated and reacted at 100 ° C. for 1 hour. To the obtained reaction solution, 15.8 g (O. lmol, l. Oeq.) Of 4-chloro-2,3-dimethylpyridine-N-oxide was added, and the mixture was heated to 110 ° C. and reacted for 2 hours. The reaction solution was allowed to cool overnight, and then lOOmL of methanol was added to the residue obtained by removing the separated toluene layer by decantation and stirred. The insoluble material was removed by filtration, and the filtrate obtained was concentrated to dryness under reduced pressure to obtain 69.2 g of 4- (6-hydroxyhexyloxy) _2,3-dimethylpyridine-N-oxide.

[0071] Synthesis Example 5: 4- (6-hydroxyhexyloxy) -2-acetoxymethyl-3_methylpyridine

4- (6-Hydroxyhexyloxy) -2,3_dimethylviridine-N-oxide 68.2g (O. lmol, l.Oeq.) And acetic anhydride 153.1g (1.5mol, 15eq.) Were added at 100 ° C. The reaction was performed for 4 hours. 4- (6-Hydroxyhexyloxy) -2-acetoxymethyl -3- by purifying 96.3 g of the concentrated residue obtained by distilling off anhydrous acetic acid by silica gel column purification (chloroform: methanol = 40: 1) 30.7 g of methylpyridine was obtained as an orange oil (yield 95.0%). [0072] Synthesis Example 6: 4- (6-hydroxyhexyloxy) -2-hydroxymethyl-3-methylpyridine

4- (6-hydroxyhexyloxy) -2-acetoxymethyl-3-methyl-4-pyridine (29.7 g, 0.092 mol, l.Oeq.) Was added to 147 g (0.736 mol, 8.0 eq.) Of 20% aqueous sodium hydroxide. The solution was added dropwise, reacted at room temperature for 1 hour, extracted with 200 mL of black mouth form, dried over magnesium sulfate, and concentrated to dryness to obtain 22.7 g of an orange-brown oil. Since the starting material was not hydrolyzed, it was further reacted at room temperature for 3 hours in a 20% aqueous sodium hydroxide solution (12.0 eq.), Then extracted with 150 mL of Kokuguchi Form, and obtained after concentration under reduced pressure. By purifying 19.0 g of a brown oily substance on a silica gel column (black mouth form), 7.1 g of 4- (6_hydroxyhexyloxy) -2-hydroxymethyl-3-methylpyridine was obtained as an oily substance (yield 58.2% ).

Synthesis Example 7: 4- (7-Hydroxyheptyloxy) -2. 3_dimethylpyridine-N-oxide

Under a nitrogen stream, 24.8 g (0.188 mol, 2.2 eq.) Of 1,7-heptanediol and lOOmL of toluene were charged in a silicon oil bath and dissolved at 60 ° C with stirring, then 3.1 g of metal Na (0.136 mol, 1.6 eq) .) Was added. Next, the silicon oil bath was heated and reacted at 100 ° C. for 1 hour. To the obtained reaction solution, 13.4 g (0.085 mol, l.Oeq.) Of 4-chloro-2,3-dimethylviridine-N-oxide was added, and then the temperature was raised to 100 ° C. and reacted for 2 hours. The reaction solution was allowed to cool overnight, and then lOOmL of methanol was added to the residue obtained by removing the separated toluene layer by decantation and stirred. The filtrate obtained after removing insolubles by filtration was concentrated to dryness under reduced pressure to obtain 45.5 g of 4- (7_hydroxyheptyloxy) -2,3-dimethylpyridine-N-oxide.

Synthesis Example 8: 4- (7-Hydroxyheptyloxy) -2-acetoxymethyl-3-methylpyridine

4- (7-Hydroxyheptyloxy) -2,3-dimethylviridine-N-oxide 44.5 g (0.085 mol, l.Oeq.) And acetic anhydride 130.2 g (1.275 mol, 15 eq.) Were added at 100 ° C. The reaction was performed for 4 hours. 4- (7-Hydroxyheptyloxy) -2-acetoxymethyl-3-methylpyridine was purified by silica gel column purification of 61.7g of the concentrated residue obtained after distilling off acetic anhydride (chloroform: methanol = 40: 1). 26.3 g was obtained as an oil (yield 91.6%).

[0075] Synthesis Example 9: 4- (7-hydroxyheptyloxy) -2-hydroxymethyl-3-methylpyridine

4- (7-hydroxyheptyloxy) -2-acetoxymethyl-3-methylpyridine (25.3 g, 0.07 5 mol, l.Oeq.) Was added dropwise to 120 g (0.6 mol, 8.0 eq.) Of a 20% aqueous sodium hydroxide solution. After reacting at room temperature for 1.5 hours, extract with 200 mL of black mouth form, dry over magnesium sulfate, and concentrate. Upon drying, 14.6 g of 4- (7-hydroxyheptyloxy) -2-hydroxymethyl-3-methylpyridine was obtained as a light brown oil (yield 76.8%).

Synthesis Example 10: 4- (8-Hydroxyoctyloxy) -2,3_dimethylviridine-N-oxide

Under a nitrogen stream, 47.4 g (0.324 mol, 3.6 eq.) Of 1,8-octanediol and lOOmL of toluene were charged in a silicon oil bath and dissolved at 60 ° C with stirring, then 4.1 g of metal Na (0.18 mol, 2.0e Added q.). Next, the silicon oil bath was heated and reacted at 100 ° C. for 1 hour. After adding 14.2 g (0.09 mol, l.Oeq.) Of 4-chloro-2,3-dimethylpyridine-N-oxide to the resulting reaction solution, the temperature was raised to 110 ° C. and reacted for 2 hours. The reaction solution was allowed to cool overnight, and then 150 mL of methanol was added to the residue obtained by removing the separated toluene layer by decantation, followed by stirring. The filtrate obtained after removing insolubles by filtration was concentrated to dryness under reduced pressure to obtain 68. lg of 4_ (8-hydroxyoctyloxy) _2,3-dimethylpyridine-N-oxide.

Synthesis Example 11: 4- (8-hydroxyoctyloxy) -2-acetoxymethyl-3-methylpyridine

4- (8-Hydroxyoctyloxy) -2,3-dimethylviridine-N-oxide 67.lg (0.09mo 1, l.Oeq.) And acetic anhydride 137.8g (1.35mol, 15eq.) Were added. The reaction was performed at ° C for 4 hours. 4- (8-Hydroxyoctyloxy) -2-acetoxymethyl -3- by purifying 98.5 g of the concentrated residue obtained after distilling off acetic anhydride by silica gel column purification (chloroform: methanol = 40: 1) 41.6 g of methylpyridine was obtained as an oil.

Synthesis Example 12: 4- (8-Hydroxyoctyloxy) -2-hydroxymethyl-3-methylpyridine

4- (8-Hydroxyoctyloxy) -2-acetoxymethyl-3-methylpyridine (40.6 g, 0.09 mol, l.Oeq.) Was added dropwise to 144 g (0.72 mol, 8.0 eq.) Of 20% aqueous sodium hydroxide. After reaction at room temperature for 1 hour, extract with 200 mL of black mouth form, dry over magnesium sulfate, and concentrate to dryness to give 4- (8-hydroxyoctyloxy) -2-hydroxymethyl-3-methylpyridine. 28.0 g was obtained as an orange-brown oil.

Synthesis Example 13: 4- (9-Hydroxynonyloxy) -2. 3_dimethylpyridine-N-oxide

Under a nitrogen stream, charge 50.0 g (0.312 mol, 4.0 eq.) Of 1,9-nonanediol and 86.7 mL of toluene in a silicone oil bath and heat to 67 ° C with stirring under a nitrogen stream. (0.156 mol, 2.0 eq.) Was added. Next, the silicon oil bath was heated and reacted at 100 ° C for 1 hour. To the obtained reaction solution, 12.3 g of 4-chloro-2,3-dimethylpyridine-N-oxide (0. 078 mol, l.Oeq.) Was added, and the temperature was raised to 109 ° C. and reacted for 5 hours. The reaction solution was allowed to stand overnight. After cooling, 130 mL of methanol was added to the residue obtained by removing the separated toluene layer by decantation and stirred. The insoluble material was removed by filtration, and the filtrate obtained was concentrated to dryness under reduced pressure to give 56.4 g of 4- (9-hydroxynonyloxy) -2,3-dimethylpyridine-N-oxide as an oil.

Synthesis Example 14: 4- (9-Hydroxynonyloxy) -2-acetoxymethyl-3_methylpyridine

4- (9-Hydroxynonyloxy) -2,3-dimethylpyridine-N-oxide 56.4g (0.078mol, l.Oeq.) And acetic anhydride 119.3g (1.169mol, 15eq.) Were added at 100 ° C. The reaction was allowed for 5 hours. Acetic anhydride was distilled off, and 91.7 g of the concentrated residue obtained was purified by silica gel column purification (chloroform: methanol = 40: 1) to give 4- (9-hydroxynonyloxy) -2-acetoxymethyl-3-methyl This gave 34.7 g of rupyridine as an oil.

Synthesis Example 15: 4- (9-Hydroxynonyloxy) -2-hydroxymethyl-3-methylpyridine

4- (9-Hydroxynonyloxy) -2-acetoxymethyl-3-methylpyridine (34.7g, 0.078mol, l.Oeq.) Was added dropwise to a 20% sodium hydroxide aqueous solution (125g, 0.625mol, 8.0eq.). After reaction at room temperature for 1 hour, extract with 173 mL of black mouth form, dry over magnesium sulfate, and concentrate to dryness to give 4- (9-hydroxynonyloxy) -2-hydroxymethyl-3-methylpyridine 28 Obtained .4 g as a brown oil.

[0082] Synthesis Example 16: 4- 0-hydroxydecyloxy) -2,3_dimethylviridine-Ν-oxide

In a nitrogen gas stream, 50.0 g (0.287 mol, 4.0 eq.) Of 1,10-decanediol and 79.7 mL of toluene were charged in a silicon oil bath, and the mixture was stirred under a nitrogen gas stream and heated to 67 ° C. .3 g (0.143 mol, 2.0 eq.) Was added. Next, the silicon oil bath was heated and reacted at 100 ° C. for 1 hour. To the resulting reaction solution, 11.3 g (0.072 mol, l.Oeq.) Of 4_chloro-2,3-dimethylpyridine-N-oxide was added, and then the temperature was raised to 109 ° C. and reacted for 3 hours. The reaction solution was allowed to stand overnight. After cooling, 120 mL of methanol was added to the residue obtained by removing the separated toluene layer by decantation and stirred. The insoluble material was removed by filtration, and the filtrate obtained was concentrated to dryness under reduced pressure to give 72.9 g of 4- (10-hydroxydecyloxy) -2,3-dimethylpyridine-N-oxide as a brown oil.

[0083] Synthesis Example 17: 4- (10-Hydroxydecyloxy) 2-2-case I: Ximel _3_2 ^ Rubidin 4- (10-Hydroxydecyloxy) -2,3-dimethylviridine-N-oxide 72.9g (0.072mol, l.Oeq.) And acetic anhydride 109.7g (1.075mol, 15eq.) Were added to 100 ° C For 4 hours. 4- (10-Hydroxydecyloxy) -2 as a mixture containing unreacted raw materials by purifying 93.5 g of the concentrated residue obtained after distilling off acetic anhydride by silica gel column purification (black mouth form: methanol = 40: 1) -Acetoxymethyl-3-methylpyridine 18.5 g of an orange-brown oil was obtained. Acetic anhydride (100.0 g, 1.021 mol, 15 eq.) Was added to orange brown oil (18.5 g), and the mixture was reacted at 100 ° C for 3 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain 20.4 g of 4_ (10-hydroxydecyloxy) -2-acetoxymethyl-3-methylpyridine.

Synthesis Example 18: 4- (10-Hydroxydecyloxy) -2-hydroxymethyl-3-methylpyridine

4- (10-Hydroxydecyloxy) -2-acetoxymethyl-3-methylpyridine (14.0 g, 0.037 mol, l.Oeq.) Was added dropwise to a 20% aqueous sodium hydroxide solution (59 g, 0.296 mol, 8.0 eq.). After overnight reaction at room temperature, extract with 10 mL of black mouth form, dry over magnesium sulfate, and concentrate to dryness to give 12.0 g of 4- (10-hydroxydecyloxy) -2-hydroxymethyl-3-methylpyridine Was obtained as an orange-brown oil.

Example 1: 2-“{4- (5-hydroxypentyloxy) -3-methylpyrid-2-yl} methylthio 1 H-benzimidazole

In a nitrogen atmosphere, 6.5 g (0.029 mol, l.Oeq.) Of 4- (5-hydroxypentyloxy) -2-hydroxymethyl-3-methylpyridin was dissolved in lOOmL of black mouth form and chlorinated while cooling with salt ice. 10.4 g (0.087 mol, 3 eq.) Of thionyl was added to a solution dissolved in 90 mL of chloroform and reacted at −10 ° C. for 3 hours. The reaction solution was adjusted to pH 9 with saturated aqueous sodium carbonate solution, extracted with 90 mL of chloroform, dried over magnesium sulfate, and concentrated to dryness to give 4- (5_hydroxypentyloxy) -2-chloromethyl- 7.8 g of 3_methylpyridine was obtained. 4_ (5-Hydroxypentyloxy) _2_Chloromethyl-3-methylpyridine 7.5g (0.029mol, l.Oeq.) And 2-mercaptobenzimidazole 3.5g (0.023mol, 0.8eq.) Then, a solution of NaOH 1.4 g (0.035 mol, 1.2 eq.) In ethanol 60 mL was added over 1.5 hours. Next, the temperature was raised to 50 ° C., the reaction was performed for 15 minutes, and the mixture was concentrated under reduced pressure to obtain 12.8 g of an orange oil. The concentrated residue was purified by silica gel column purification (black mouth form: methanol = 40: 1) to obtain 4.8 g of an orange oil. By recrystallizing the oil with ethyl acetate: methanol = 20: 1 (21vol) , 2-[{4- (5-hydroxypentyloxy) -3-methylpyridine-2-yl} methylthio] -1Η-benzimidazole colorless crystals 2.8 g were obtained (HPLC: 99.4Area%, yield) 26.9%).

'H-NMR (400MHZ, CDCl) δ: 1.47-1.73 (7Η, m), 2.25 (3Η, s), 3.70 (2H, t J = 6

Three

Hz), 4.03 (2H, t J = 6Hz), 4.37 (2H, s), 6.72 (1H, d J = 6 Hz), 7.08-7.24 (2H, m), 7.33-7.85 (2H, m), 8.33 (1H, d J = 6 Hz), 12.52-13.43 (1H, bs)

MS m / z: 357 (M ⁺ )

Example 2: 2-"{4- (6-Hydroxyhexyloxy) -3-methylpyridine_2-yl} methylthio チオ -1H-benzimidazole

In a nitrogen atmosphere, 6.9 g (0.029 mol, l.Oeq.) Of 4_ (6-hydroxyhexyloxy) _2 -hydroxymethyl-3-methylpyridin was dissolved in 120 mL of dichloromethane, and 10.4 g (0.087 mol, 3 eq.) Of thionyl chloride was dissolved. ) In 60 mL of dichloromethane was added and reacted at _10 ° C for 1.5 hours. The reaction solution was adjusted to pH 8 with a saturated aqueous solution of sodium carbonate, and the dichloromethane layer was dried over magnesium sulfate and concentrated to dryness to give 4- (6-hydroxyhexenoleoxy) -2-chloromethyl as an orange oil. 6.7 g of 3-methylpyridine was obtained (yield 89.3%). 4_ (6_hydroxyhexyloxy) -2-chloromethyl-3-methylpyridine 6.5g (0.025mol, l.Oeq.) And 2_mercaptobenzimidazole 3.5g (0.023mol, 0.8eq.) To this solution, a solution of NaOH 1.4 mL (0.035 mol, 1.2 eq.) In ethanol 60 mL was added over 1.5 hours. Subsequently, the temperature was raised to 50 ° C., the reaction was performed for 15 minutes, and the solution was concentrated under reduced pressure to obtain 12.8 g of an orange oily substance. The concentrated residue was subjected to silica gel column purification (black mouth form: methanol = 40: 1) to obtain 4.8 g of an orange oil. 2-[{4- (5-Hydroxyhexyloxy) -3-methylpyridin-2-yl} methylthio]-by recrystallizing the oil with ethyl acetate: methanol = 20: 1 (21 vol) As a result, 2.8 g of 1-benzimidazole colorless crystals were obtained (HPLC: 99.4 Area%, yield 26.9%).

'H-NMR (400MHZ, CDCl) δ: 1.34-1.99 (9Η, m), 2.26 (3Η, s), 3.67 (2H, t J = 6

Three

Hz), 4.03 (2H, t J = 6Hz), 4.37 (2H, s), 6.73 (1H, d J = 6 Hz), 7.11-7.24 (2H, m), 7.33-7.77 (2H, m), 8.34 (1H, d J = 6 Hz), 12.69-13.34 (1H, bs)

MS m / z: 371 (M ⁺ )

Example 3: 2-"{4- (7_hydroxyheptyloxy) -3-methylpyridin-2-yl} methylthio チオ -1H-benzimidazole 4- (7-Hydroxyheptyloxy) -2-hydroxymethyl-3-methylpyridine 8.1 g (0.032 mol, l.Oeq.) Was dissolved in 120 mL of dichloromethane, and 11.4 g (0.096 mol, 3.0eq-) thionyl chloride was dissolved. And reacted at _10 ° C for 2 hours. The reaction solution was adjusted to pH 8 with saturated aqueous sodium carbonate solution, and the dichloromethane layer was dried over magnesium sulfate and concentrated to dryness to give 4- (7_hydroxyheptyloxy) -2-chloromethyl- 3-methylpyridine 8 • 7 g was obtained.

To a solution of 2-mercaptobenzimidazole 3.6 g (0.024 mol, 0.8 eq.) And 28% sodium methoxide 6.9 g (0.036 mol, 1.2 eq.) Dissolved in methanol lOOmL, add 4_ (7_hydroxyheptyloxy). ) A solution of 8.2 g of _2_chloromethyl-3_methylpyridine in 10 mL of methanol was prepared at 27 ° C. Subsequently, the mixture was heated to reflux for 30 minutes, cooled, and concentrated under reduced pressure to obtain 9.0 g of an orange oil. The concentrated residue was dissolved by adding 200 mL of ethyl acetate and 12 g of methanol, and then the organic layer was washed with 15 OmL of water and washed with water. The aqueous layer was extracted with a 50mU trowel of ethyl acetate, and the organic layers were combined. To the combined organic layers, 27 g of silica gel was added and stirred for 30 minutes, and the silica gel was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 8.4 g of orange-white crystals. The crystals were suspended in 126 g (15 vol) of ethyl acetate, heated to 57 ° C., and 2.0 g of methanol was added to completely dissolve the crystals. Crystals precipitated by cooling. After aging at 20 ° C for 30 minutes, the crystals were collected by filtration and dried under reduced pressure to give 2-[{4- (7-hydroxyheptyloxy) -3-methylpyridine-2-yl} methylthio] -1H -4.0g colorless crystals of benzimidazole were obtained (HPLC purity: 98.2Area%, yield 34.5%)

'H-NMR (400MHZ, CDCl) δ: 1.30—1.99 (11H, m), 2.25 (3H, s), 3.66 (2H, t J = 6

Three

Hz), 4.02 (2H, t J = 6Hz), 4.37 (2H, s), 6.72 (1H, d J = 6 Hz), 7.10-7.25 (2H, m), 7.31-7.81 (2H, m), 8.33 (1H, d J = 6 Hz), 12.61-13.45 (1H, bs)

MS m / z: 385 (M ⁺ )

Example 4: 2-"{4- (8-hydroxyoctyloxy) -3-methylpyridine_2-yl} methylthioΊ-1H-benzimidazole

4- (8-hydroxyoctyloxy) -2-hydroxymethyl-3-methylpyridine (27.0 g, 0.09 mol, l.Oeq.) Was dissolved in dichloromethane (140 mL), and thionyl chloride (21.4 g, 0.18 mol, 2.0 eq) was dissolved. .) Was added and reacted at _10 ° C for 3.5 hours. The reaction solution was adjusted to pH with 300 g of saturated aqueous sodium carbonate solution. After adjusting to 8, the dichloromethane layer was dried over magnesium sulfate and concentrated to dryness to give 25.2 g of 4- (8-hydroxyoctyloxy) -2-chloromethyl-3-methylpyridin as an orange-brown oil. Obtained (yield 98.1%).

[0087] 4.8 g (0.032 mol, 0.8 eq.) 2-mercaptobenzimidazole and 28% sodium methoxide 9.

3 g (0.048 mol, 1.2 eq.) Dissolved in methanol lOOmL was stirred into 4_ (8_hydroxyoctyloxy) _2_chloromethyl-3_methylpyridine 11.4 g (0.04 mol, l.Oeq.) In methanol. The solution dissolved in mL was added at 27 ° C. Subsequently, the mixture was heated to reflux for 30 minutes, cooled, and concentrated under reduced pressure to obtain 22.8 g of an orange oil. The concentrated residue was dissolved in 250 mL of ethyl acetate, and the organic layer was washed with 20 OmL of water. Since the organic layer was allowed to stand overnight and crystals were precipitated, 20 mL of methanol was dissolved by heating at 42 ° C, then 27.6 g of silica gel was added and stirred for 30 minutes, and then the silica gel was filtered off. . The filtrate was concentrated under reduced pressure to obtain 9.0 g of orange-white crystals. The crystals were suspended in 135 g (15 vol) of ethyl acetate and heated to 57 ° C., and then 12.8 g of methanol was added to completely dissolve the crystals. Crystals precipitated by cooling. After aging at 20 ° C for 1 hour, the crystals were collected by filtration. The crystals were dried under reduced pressure to obtain 3.7 g of colorless crystals of 2-[{4- (8-hydroxyoctyloxy) -3-methylpyridine-2-yl} methylthio] -1Η-benzimidazole. (HPLC purity: 98.4Area%, yield 23.1%).

[0088] 'H-NMR (400MHZ, CDCl) 5: 1.10-1.95 (13H, m), 2.26 (3H, s), 3.65 (2H, t J = 6

Three

Hz), 4.02 (2H, t J = 6Hz), 4.37 (2H, s), 6.73 (1H, d J = 6 Hz), 7.11-7.24 (2H, m), 7.44-7.64 (2H, m), 8.33 (1H, d J = 6 Hz), 12.26-13.84 (1H, bs)

MS m / z: 399 (M ⁺ )

Example 5: 2-“{4- (9-Hydroxynonyloxy) -3-methylpyridin-2-yl-tylthio 1 H-benzimidazole

4- (9-Hydroxynonyloxy) -2-hydroxymethyl-3-methylpyridine (28.4 g, 0.078 mo 1, l.Oeq.) Was dissolved in 121 mL of dichloromethane, and 18.5 g (0.155 mol, 2.0 eq. ) Was dissolved in 69 mL of dichloromethane and reacted at _17 ° C for 3 hours. The reaction mixture was adjusted to pH 9 with saturated aqueous sodium carbonate solution, and the extracted dichloromethane layer was dried over magnesium sulfate and concentrated to dryness to give 4- (9-hydroxynonyloxy) -2-chloromethyl -3- 17.2 g of methylpyridine was obtained (yield 74.1%). [0089] 2-mercaptobenzimidazole (7.2 g, 0.048 mol, 0.6 eq.) And 28% sodium methoxide (14.0 g, 0.073 mol, 0.93 eq.) Were dissolved in 181 mL of methanol. Hydroxynonyloxy) -2-chloromethyl-3-methylpyridine (17.2 g, 0.057 mol, l.Oeq.) Was added at 27 ° C. Next, the mixture was heated to reflux for 30 minutes, cooled, and concentrated under reduced pressure to give an orange oil. The concentrated residue was dissolved in 377 mL of ethyl acetate, and the organic layer was washed with 302 mL of water. Since crystals were precipitated in the organic layer, 30 mL of methanol was dissolved at 35 ° C. at room temperature, 41.6 g of silica gel was added and stirred for 30 minutes, and the silica gel was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 13.9 g of an orange oil. After heating and dissolving with 208.5 g (15 vol) of ethyl acetate, crystals were deposited by cooling. After aging at 20 ° C for 1 hour, the crystals were collected by filtration. The crystals were dried under reduced pressure to obtain 4.3 g of 2-[{4- (9_hydroxynonyloxy) -3-methylpyridine_2-yl} methylthio] -1H-benzimidazole pale yellow crystals ( HPLC purity: 96.4 Area%, yield 17.7%). 'H-NMR (400MHZ, CDCl) δ: 1.19-1.90 (15H, m), 2.26 (3H, s), 3.64 (2H, t J = 6

Three

Hz), 4.02 (2H, t J = 6Hz), 4.37 (2H, s), 6.73 (1H, d J = 6 Hz), 7.11-7.24 (2H, m), 7.36-7.66 (2H, m), 8.33 (1H, d J = 6 Hz), 12.40-13.60 (1H, bs)

MS m / z: 413 (M ⁺ )

Example 6: 2-"{4- (10-hydroxydecyloxy) -3-methylpyridin-2-yl} methylthio 1 -1Η-benzimidazole

4- (10-Hydroxydecyloxy) -2-hydroxymethyl-3-methylpyridine 11.5 g (0.035 mol, l.Oeq.) Is dissolved in 120 mL of dichloromethane, and 12.5 g (0.105 mol, 3.0 eq.) Of thionyl chloride is dissolved. A solution of 60 mL of dichloromethane was added and reacted at -17 to -12 ° C for 3 hours. The reaction solution was adjusted to pH 8 with a saturated aqueous sodium carbonate solution, and the extracted dichloromethane layer was dried over magnesium sulfate and concentrated to dryness to give 4_ (10-hydroxydecyloxy) -2-chloromethylol-3- 10.6 g of methylpyridine was obtained (yield 96.4%).

[0090] 4.3 g (0.029 mol, 0.9 eq.) 2-mercaptobenzimidazole and 4.3 g (0.029 mol, 0.9 eq.) 4- (10-hydroxydecyloxy) _2_chloromethyl-3-methylpyridine and methanol To 20 OmL of solution, 28% sodium methoxide 6.8g (0.035mol, l. Leq.) 22 Added in C. Subsequently, the mixture was heated to reflux for 30 minutes, cooled and concentrated under reduced pressure to obtain 18.0 g of an orange oil. The concentrated residue is dissolved in a mixture of 250 mL of ethyl acetate and 2 mL of methanol, and then added with 200 mL of water. The machine layer was washed with water. To the organic layer, 18.0 g of silica gel was added and stirred for 30 minutes, and then the silica gel was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 13.4 g of yellowish white crystals. The crystals were suspended in 201 g (15 vol) of ethyl acetate, heated to 55 ° C., and 17.5 g of methanol was added to completely dissolve the crystals. Crystals precipitated by cooling. After aging at 10-15 ° C for 30 minutes, 6.5 g of crystals were collected by filtration. The crystals were added with 280 g (43 times amount) of methanol and stirred with heating. Insoluble matter was removed by filtration, followed by concentration drying under reduced pressure to obtain 6.7 g of pale yellow crystals. The crystals were heated and melted at 60 ° C with 134 g (20 times the amount) of ethyl acetate and 6.7 g of methanol and allowed to cool. After stirring overnight at 201 ° C, the crystals were collected by filtration and dried under reduced pressure to give 2-[{4_ (10-hydroxydecyloxy) _3_methylpyridine-2-yl} methylthio] -1H-benzimidazole. Of colorless crystals were obtained (HPLC purity: 96.3 Area%, yield 36.5%).

[0091] 'H-NMR (400MHZ, CDCl) δ: 1.10—1.95 (17H, m), 2.26 (3H, s), 3.64 (2H, t J = 6

Three

Hz), 4.02 (2H, t J = 6Hz), 4.37 (2H, s), 6.73 (1H, d J = 6 Hz), 7.11-7.24 (2H, m), 7.44-7.64 (2H, m), 8.33 (1H, d J = 6 Hz), 12.30-13.68 (1H, bs)

MS m / z: 427 (M ⁺ )

麵言續列 1

Antibacterial activity test

(Method)

H. pylori was tested in vitro on Columbia agar using ATCC 43504, a standard strain. The culture was carried out using a Columbia agar medium at 37 ° C, pH 7.0 for 3 days, and the minimum inhibitory concentration (MIC, μg / ml) was determined on the 4th day. Each specimen was dissolved in 1% DMSO solution. In addition, penicillin ampicillin (control drug 1), aminoglycoside gentamicin (control drug 2), tetracycline tetracycline (control drug 3), and new quinolone ofloxacin (control drug 4) are used as antibiotic control drugs. It was.

[0092] (Result)

The results are shown in Table 1 as anti-helicopactor 'pylori activity (MIC (x g / ml)) in vitro.

[table 1] In vitro anti-helicopacter's pylori activity of a novel pyridine derivative

As a result of this test, the compounds of the present invention (Examples 1 to 6) were found to have a strong bactericidal effect against H. pylori as well as various antibacterial agents (control agents 1 to 4).

[0094] In addition, anti-helicopacter pylori activity (MIC (μg / ml)) is clearly more than 10 times stronger than the existing similar two-compounds (comparative compounds 1 and 2). It was found that anti-helicopacter 'pylori activity was exhibited. The compounds of the comparative examples are the above-mentioned 2-[{4- (2-hydroxyethoxy) -3-methylbilidine-2-yl} methylthio] -m-benzimidazole (Comparative Compound 1) and 2-[{4 -(3-Hydroxypropoxy) -3-methylpyridine-2-yl} methylthio] -1H-benzimidazole (Comparative Compound 2).

[0095] Pharmacological test example 2

(Method)

H. pylori was developed in Colombia using NCTC 11637, 11916, which is the standard strain, PT # 1045482, ΡΤ # 1045483, ΡΤ # 1045484, which is the clinical isolate, and clinical isolates オフ 2, 4, and 5 that are resistant to ofloxacin and roxithromycin. In vitro tests were performed on agar medium. Each specimen was dissolved in 1% DMSO solution. In addition, macrolide roxithromycin and new quinolone ofloxacin were used as antibiotics. The cells were cultured at 37 ° C and pH 7.0 for 3 days, and the minimum inhibitory concentration (MIC, μg / ml) was determined on the 4th day. [0096] (Result)

The results are shown in Table 2 as the effect against Helicopactor 'pylori-resistant bacteria in vitro (MIC g / ml)).

[Table 2] Effects of new pyridine derivatives on Helicobacter pylori resistant bacteria

In Table 2, each numerical value is the minimum inhibitory concentration (MIC, μg / ml) of each specimen for each bacterial species, RXM represents roxithromycin, and OFLX represents ofloxacin.

[0098] From the results of this test, the compounds of the present invention (Examples 1 to 6) showed antibacterial activity equivalent to or stronger than roxithromycin and ofloxacin against standard strains and clinical isolates. Furthermore, it showed strong antibacterial activity against clinical isolates resistant to roxithromycin and ofloxacin. That is, it was revealed that the antibacterial activity was also strong against the resistant strains of macrolide roxithromycin and new quinolone ofloxacin.

[0099] Table 3 below shows the minimum inhibitory concentrations (MIC, μg / ml) of the compounds having the structure similar to the compound of the present invention ((a) to (f)) against the standard strains NCTC11637 and NCTC11916. . These are the data described in Table 6 of JP-A-7-69888.

[Table 3] Effects of existing pyridine derivatives on Helicobacter pylori

[0100] In Table 3, (a) is 5-methoxy-2- (4-methoxy-3,5_dimethylviridine-2_yl) methylsulfinyl-1H-benzimidazole, and (b) is 5-methoxy- 2- (4-Methoxy-3,5-dimethylviridine-2-yl) methylthio-1H-benzimidazole, (c) is 2- [3-Methyl-4- (2, 2, 2_trifluoroethoxy) pyridine -2-yl] methylsulfier-1H-benzimidazole, (d) is 2- [3-methyl-4- (2,2,2-trifluoroethoxy) pyridine-2-yl] methylthio- 1H-benzimidazole, (e) is 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methylsulfiel--benzimidazole sodium salt, (f) is 2- [ 4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methylthio-1H-benzimidazole, RXM is roxithromycin, and each value is the minimum growth inhibitory concentration of each specimen for each bacterial species (MIC, z g / ml) it is.

[0101] From the comparison of the data in Table 2 and Table 3, the compounds of the present invention (Examples 1 to 6) are more resistant to the standard strain NCTC11637 than the same strains of compounds ((a) to (f)). It can be seen that it has about 2.7 to 1,667 times the activity and about 5.2 to 1,667 times the activity against NCTC11916. In particular, Example 4 was found to be 26.6 times stronger in the standard strain NCTC1 1637 and 52 times stronger in the standard strain NCTC11916 than (e) (f), which is the most active among the compounds of the same strain.

[0102] 觀试隨 3

(Method)

In vitro antibacterial tests against various bacteria were conducted on the compounds of Examples 1 to 6. Gram-negative bacteria include E. coli (ATCC 10536, ATCC 25922), Klebsiella pneumonia (AT 1031), Proteus vulgans (ATC 13315), Pseudomonas aerugmosa (ATC 9027), Salmonella typhimurium (ATC C 13311), As the euhumic fungus, Staphylococcus aure us, MRSA (AT C 33591), Staphylococcus epidermidis (ATC 12228), treptococcus pneumonia (ATCC 6301), Mycobacterium ranae (ATCC 110), Enterococcus faecalis (VRE, ATCC 51575) Was used. Various bacteria are cultured in the usual way at 37 ° C for 20 to 48 hours. The minimum inhibitory concentration (MIC, / g / ml) was determined. Each specimen was dissolved in 1% DMSO solution. In addition, aminoglycoside gentamicin (GEM) was used as an antibiotic control. (result)

The results are shown in Table 4 as the effects on various bacteria in vitro (MIC (x g / ml)).

[Table 4] Effects of new pyridine derivatives on Gram-negative and Gram-positive bacteria (μg / ral)

As a result of the test, all of the compounds of Examples 1 to 6 were various gram-negative bacteria and gram-positive. No antibacterial action was observed in the fungus. On the other hand, aminoglycoside gentamicin showed strong antibacterial activity against various gram-negative and gram-positive bacteria. This suggests that the compound of the present invention has no effect on enterobacteria.

Translation

Compound of Example 3 50.0mg

Mannito Nore 65.5mg

! ―2.5mg

Crystalline cellulose lO.Omg

Corn starch lO.Omg

Carboxymethylcellulose 'Calcium 5.0mg

Talc 2.0mg

Magnesium stearate 0.2mg

In accordance with a conventional method at the above blending ratio, 145.2 mg tablets per tablet were prepared.

[0106] Formulation Example 2 Granules

300 mg of the compound of Example 4

Lactose 540mg

lOOmg

/ ヽ 'z—su 50mg

Tanorek 10mg

With the above blending ratio, according to a conventional method, 1OOOmg granule was prepared per packet.

[0107] Formulation Example 3 Capsule

Compound of Example 5 50mg

Lactose 15mg

Corn starch 25mg

Microcrystalline cellulose 5mg

'"Magnesium silicate 1.5mg

96.5 mg capsules per capsule were prepared at the above blending ratio according to a conventional method.

[0108] Steelmaking II example 4 泮射吝 II Compound of Example 5 lOOmg

Sodium chloride 3.5mg

Suitable amount of distilled water for injection

(2ml per ampoule)

An injection was prepared according to a conventional method at the above blending ratio.

[0109] Formulation Example 5 Syrup

Compound of Example 5

Refined white sugar

Ethyl parahydroxybenzoate

Butyl parahydroxybenzoate

Appropriate amount of purified water

A syrup was prepared at the above blending ratio according to a conventional method.

[0110] Formulation Example 6 Tablet

Compound of Example 5 50mg

'20mg

2bmg

Microcrystalline cellulose 5mg

r ~~ su 5mg

Tanorek 2mg

Magnesium stearate 2mg

Tablets of l lOmg per tablet were prepared at the above blending ratio according to a conventional method.

Industrial applicability

[0111] The novel pyridine derivative and the pharmaceutically acceptable salt thereof of the present invention do not act on human resident bacteria, exhibit not only a specific antibacterial activity against H.pyroli, but also resistance to antibacterial agents. Since it exhibits strong antibacterial activity against strains, it is an extremely promising medicine.

[0112] All publications, patents and patent applications cited in this specification are used as is for reference.

Claims

Claim [1] General formula (I)

[Chemical 1]

Wherein R is a novel pyridine derivative represented by a straight chain or branched chain (representing a group) having 5 to 10 carbon atoms or a pharmaceutically acceptable salt thereof.

[2] Formula (II)

[Chemical 2]

And the general formula (III)

[Chemical 3]

(Wherein R represents a linear or branched hydroxyalkyl group having 5 to 10 carbon atoms, and X represents a halogen atom or a sulfonoxy group). General formula (I)

[Chemical 4]

(Wherein R represents the same meaning as described above), or a pharmaceutically acceptable salt thereof.

[3] A pharmaceutical composition comprising the novel pyridine derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

[4] An anti-helicopacter pylori agent comprising the novel pyridine derivative or a pharmaceutically acceptable salt thereof according to claim 1.

[5] The anti-helicopacter pylori agent according to claim 4, wherein the target Helicopacter pylori is a resistant bacterium to a macrolide antibiotic or a new quinolone antibiotic.

[6] The anti-helicopacter pylori agent according to claim 4, further comprising one or more dextrins.

[7] The pile helicopter pylori agent according to claim 4, further comprising one or more drugs for suppressing secretion of gastric acid.

[8] A prophylactic or therapeutic agent for a disease associated with Helicopacter pylori comprising the novel pyridine derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[9] The disease is gastritis, gastric ulcer, duodenal ulcer, non-ulcer dyspepsia syndrome, gastric MALT lymphoma, gastric hyperplasia polyp, gastric cancer, digestive organ cancer, knee inflammation, or inflammatory bowel disease. The preventive or therapeutic agent as described.

10. The prophylactic or therapeutic agent according to claim 9, wherein the gastric cancer is gastric cancer that occurs after endoscopic resection of early gastric cancer.

[11] Any one of claims 8 to 10, further comprising one or more dextrins

The preventive or therapeutic agent according to item 1.

[12] The method according to any one of claims 8 to 8, further comprising one or more drugs for suppressing secretion of gastric acid

11. The preventive or therapeutic agent according to any one of 10 above.